Scientists in the UK, Portugal and Germany solved the structure of kynurenine 3-monooxygenase (KMO), a protein implicated in the neurodegeneration (destruction of nerve cells) seen in diseases associated with old age, such as Alzheimer’s, Parkinson’s and Huntington’s.
It also reveals how to block KMO in a major first step to develop a promising new therapeutic approach for a group of diseases that, despite affecting millions worldwide, remain without cure or treatment.
Old lady at San Miguel Allende, Guanajuato, Mexico. Credit: Tomas CastelazoKMO is a protein, part of a cascade of reactions called kynurenine path (KP), which is known to be able to cause neurodegeneration. The cascade breakdowns tryptophan - an important molecule for brain activity - into a series of metabolites, some of which are neuroprotective (the metabolite called KYNA), while others are toxic to the nerve cell (called 3-HK and QUIN).
The theory is that with age the balance moves towards more neurotoxic compounds leading to the neurodegeneration seen in diseases linked to aging.
Supporting this idea not only the neurotoxic HK and QUIN are found in abnormally high quantities in the brain of neurodegenerative patients, but also, when injected into animals, reproduce many of the pathological features and chemical impairments typical of neurodegenerative diseases. The levels of KYNA (which is neuro-protective), on the other hand, are low in these patients’ brains.
What this suggests is that correction of the neurotoxic/neuroprotective imbalance could be beneficial in stopping the brain destruction linked to aging (and old people's neurodegenerative diseases).
And for that KMO is the perfect target -it seats at the branching point between the two possible outcomes, catalyzing the neurotoxic arm of KP. So its inhibition/blocking should swerve tryptophan breakdown towards the neuroprotective product (KYNA).
And indeed, blocking KMO ameliorates symptoms in several animal models of Huntington’s and Alzheimer’s disease, and this in animals asdifferent as fruit flies, yeast and even mice. A problem for its use inpatients, though, is that none of the existing KMO inhibitors can enter the brain easily limiting their therapeutic worth in humans. It is here that Marta Amaral, a doctoral student co-supervised by researchers Nigel Scrutton, Flaviano Giorgini, and TiagoOuteiro - steps in.
The researcher used a crystallography to determine KMO structure - creating crystals from biological molecules and then analyze them by X-rays is probably the most advanced technique available to obtain structural information about biological active molecules. The x-ray allows to see them as they look in “real life”,when they are functional, and so to understand better how these molecules work.
In the study to be published Amaral and colleagues describe the first crystal structure ofKMO binding its inhibitor UPF648. UPF648 can improve (in animals) the symptoms of Huntington’s disease, a neurodegenerative genetic disorder (linked to aging) that affects muscle coordination and creates cognitive decline and psychiatric problems. This is believed to happen because, even if UPF648 cannot enter the brain, the KP metabolites formed can. So as KMO is inhibited and the neuroprotective KYNA quantity increases, KYNA enters the brain, switching its balance towards neuroprotection.
But with the new results identifying where and how KMO can be blocked, scientists can now try to develop inhibitors that actually enter the brain. This will no doubt increase enormously their therapeutic effectiveness what is great news. After all, neurodegenerative conditions linked to old age are on the fast rise in developed countries where the aging population is growing without stop. At the moment, 16% of all Europeans are already over 65 (the moment when these diseases’ incidence increases abruptly), with numbers expected to reach 25% by 2030. And these come with serious financial burden – just in the UK dementia alone is costing the state £17 billion pounds a year.
The work was a collaboration between the University of Manchester, the University of Leicester University, UK, and the Institute of Molecular Medicine in Lisbon, Portugal, and the University Medical Center Goettingen, Germany.
Citation: Marta Amaral,Colin Levy, Derren J. Heyes, Pierre Lafite, Tiago F. Outeiro, FlavianoGiorgini, David Leys and Nigel S. Scrutton , Structural basis of inhibition in the neurodegeneration target kynurenine 3-monooxygenase Nature DOI: 10.1038/nature12039